Summary: Recruitment to date remains strong within the Vasculitis Natural History Study. All patients seen at the NIH Clinical Center receive comprehensive clinical evaluation and contribute samples to a growing biobank. Over the last year, we have focused upon three forms of vasculitis: drug-induced vasculitis, large vessel vasculitis (LVV), and relapsing polychondritis (RP). In terms of drug-induced vasculitis, we have focused on levamsiole, an anti-helminth drug that has recently been implicated in cases of drug-induced autoimmunity in humans exposed to cocaine adulterated with levamisole for profit. The United States Drug Enforcement Agency estimates that approximately 75% of cocaine within the US has been contaminated with levamisole. We discovered that levamisole induces neutrophil extracellular trap (NET) formation through engagement of muscarinic receptors on the surface of neutrophils. Through animal models we defined that the M3 muscarinic receptor specifically is triggered by levamisole. In collaboration with colleagues from the National Institute of Drug Abuse and colleagues from the University of California, San Francisco, we studied sera from cohorts of patients actively using cocaine contaminated with levamisole to identify novel autoantibodies against NET components. We also studied the effects of levamisole and NETs on vascular endothelial cells and found that levamisole-induced NETs were toxic to endothelial cells in vitro and in aortic myogram models. These data suggest that NETs are a source of autoantigens in levamisole-induced autoimmunity, contribute to vascular damage, and that heretofore uncharacterized interactions between the cholinergic nervous system and neutrophils may play a causal role in autoantibody formation and autoimmune disease. This work was published in JCI Insight in February 2017. In terms of LVV, we continue to recruit patients with these rare diseases. To date, we have performed whole body PET scans and angiography on approximately 80 patients with LVV. We have discovered vascular abnormalities on PET scans suggestive of ongoing subclinical vascular inflammation in a subset of patients with LVV (approximately 50%) who clinically were thought to be in disease remission. These findings are intriguing because a subset of patients with LVV are known to develop life-threatening vascular complications including aortic aneurysms and dissections late into the course of disease. The first publication from this work is currently under revision. Four imaging abstracts from this cohort were submitted to the 2017 American College of Rheumatology Annual Meeting. In the lab, we are studying the immunology of subclinical vascular inflammation in LVV. Preliminary findings from in vitro studies indicate that metabolism is altered in specific immune cell populations in association with PET scan findings in patients with LVV. In a subset of patients with LVV in our cohort, we continue to purify immune cell populations using cell sorting techniques. We are analyzing data from RNA sequencing experiments on the different cell populations in association with radiographic and clinical outcomes as a means to discover novel markers of disease activity and potentially novel therapeutic targets. In terms of relapsing polychondritis, we have recruited 35 patients with this rare disease. We are currently developing classification criteria for this disease and defining an optimal clinical approach to assessment and treatment of this condition. As part of these efforts, we have formed the first International Working Group in Relapsing Polychondritis, dedicated to collaborative clinical and translational research in this disease.